Acetyl-CoA carboxylase (ACC) activity is responsible for the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. This reaction proceeds in two half-reactions: a biotin carboxylase reaction and a carboxyltransferase reaction. Malonyl-CoA is the carbon donor in the synthesis of long chain fatty acids and in their elongation into very long chain fatty acids, and is also a regulator of the palmitoyl-CoA-carnitine shuttle system that is involved in the mitochondrial oxidation of long chain fatty acids (Harwood, Curr. Opin. Investig. Drugs, 2004, 5, 283-289; McGarry et al., J. Biol. Chem., 1978, 253, 8294-8300).
Malonyl-CoA, the product of ACC activity, is the key metabolic signal for the control of fatty acid oxidation and synthesis in response to dietary changes. The carboxylases are highly regulated by diet, hormones, and other physiological factors. Food intake induces the synthesis of ACC and increases ACC activity. Starvation or diabetes mellitus represses the expression of the genes and decreases the activities of the enzymes. Treating diabetic animals with insulin increases the activity of the enzyme, and prolonged insulin treatment stimulates the synthesis of ACC protein.
ACC exists as two tissue-specific isozymes: ACC1 (also known as acetyl-CoA carboxylase alpha; ACAC; ACACA; and tgf) which is present in lipogenic tissues such as liver and adipose and ACC2 (also known as acetyl-Coenzyme A carboxylase beta, ACACB, ACCB, HACC275, and acetyl-CoA carboxylase 2) which is present in oxidative tissues such as liver, heart and skeletal muscle. ACC1 and ACC2 are encoded by separate genes (Harwood, Curr. Opin. Investig. Drugs, 2004, 5, 283-289).
Use of antisense oligonucleotides to decrease ACC1 and ACC2 for therapeutics is advantageous over small molecules in that antisense oligonucleotides will not decrease ACC levels in the central nervous system or pancreas, thus preventing side effects observed with small molecule inhibition of ACC1 and ACC2.